Citation:

Gilbert, M., I. Hassan, C. Wood, K. OShaughnessy, S. Spring, S. Thomas, AND J. Ford. Gestational Exposure to the NIS Inhibitor Ammonium Perchlorate – Thyroid Hormones in Gland, Serum, Fetal Rat Brain. Society of Toxicology, San Diego, California, March 27 - 31, 2022.

Impact/Purpose:

This work was conducted to provide quantitative information for the refinement of Adverse Outcome Pathways for thyroid disrupting chemicals and their potential impact on developing brain. Dose-response relationships between maternal and fetal hormone concentrations in serum, thyroid gland ,and brain are described. A conceptual model of dosimetry and AOP for chemical inhibition of the sodium iodine symporter (NIS) using perchlorate as the model chemical is presented. These data and the key events described in the model will facilitate the translation of highthroughput NIS assay outputs to in vivo effects meaningful for regulatory assessment.

Description:

Adequate supplies of iodine are essential for production of the iodinated hormones of the thyroid gland. A number of environmental contaminants have been identified that interfere with the transport of iodine into the thyroid gland with the potential to reduce thyroid hormone (TH) synthesis. As thyroid hormones are critical for brain development, the effects of environmental exposures during pregnancy have raised concern for this action of environmental contaminants to impair fetal brain development. The goal of this study was to define dose response profiles of TH in the maternal and fetal compartments of pregnant rats in response to perchlorate, a reference chemical known to inhibit the sodium-iodine symporter (NIS).  Pregnant rat dams were exposed to perchlorate in the drinking water from gestational day (GD) 6-20. Blood was sampled from the dams on GD16 and from dams and fetuses at sacrifice on GD20. Thyroid glands and brain were collected on GD20 for hormone and analysis of expression of TH-responsive genes. Maternal TH in the thyroid gland and serum were reduced in a dose-dependent fashion, with steeper declines observed in the fetus. TH were also reduced in the fetal brain. Gene expression changes in the gland revealed perturbations of thyroid hormone action with differential sensitivity in dam and fetus.  Concentrations of TH in the fetal brain were reduced at the higher concentrations, while expression of TH-regulated genes in the fetal cortex was altered at all dose levels of perchlorate. These findings add to our quantitative understanding of NIS inhibition and TH production in the maternal and fetal thyroid gland. They provide a framework to support development of a quantitative Adverse Outcome Pathway (AOP) for NIS-related thyroid hormone disruption and neurodevelopment which may facilitate the translation of in vitro bioactivity to the downstream in vivo consequences of NIS inhibition in the developing fetus. Does not reflect EPA policy.

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